Inflammatory reactions occur in the brain in various CNS diseases, including autoimmune, neurodegenerative, and epileptic disorders. Proinflammatory and antiinflammatory cytokines and related ...molecules have been described in CNS and plasma, in experimental models of seizures and in clinical cases of epilepsy. Inflammation involves both the innate and the adaptive immune systems and shares molecules and pathways also activated by systemic infection. Experimental studies in rodents show that inflammatory reactions in the brain can enhance neuronal excitability, impair cell survival, and increase the permeability of the blood–brain barrier to blood‐borne molecules and cells. Moreover, some antiinflammatory treatments reduce seizures in experimental models and, in some instances, in clinical cases of epilepsy. However, inflammatory reactions in brain also can be beneficial, depending on the tissue microenvironment, the inflammatory mediators produced in injured tissue, the functional status of the target cells, and the length of time the tissue is exposed to inflammation. We provide an overview of the current knowledge in this field and attempt to bridge experimental and clinical evidence to discuss critically the possibility that inflammation may be a common factor contributing, or predisposing, to the occurrence of seizures and cell death, in various forms of epilepsy of different etiologies. The elucidation of this aspect may open new perspectives for the pharmacologic treatment of seizures.
Summary
The blood–brain barrier (BBB) is located within a unique anatomic interface and has functional ramifications to most of the brain and blood cells. In the past, the BBB was considered a ...pharmacokinetic impediment to antiepileptic drug penetration into the brain; nowadays it is becoming increasingly evident that targeting of the damaged or dysfunctional BBB may represent a therapeutic approach to reduce seizure burden. Several studies have investigated the mechanisms linking the onset and sustainment of seizures to BBB dysfunction. These studies have shown that the BBB is at the crossroad of a multifactorial pathophysiologic process that involves changes in brain milieu, altered neuroglial physiology, development of brain inflammation, leukocyte–endothelial interactions, faulty angiogenesis, and hemodynamic changes leading to energy mismatch. A number of knowledge gaps, conflicting points of view, and discordance between clinical and experimental data currently characterize this field of neuroscience. As more pieces are added to this puzzle, it is apparent that each mechanism needs to be validated in an appropriate clinical context. We now offer a BBB‐centric view of seizure disorders, linking several aspects of seizures and epilepsy physiopathology to BBB dysfunction. We have reviewed the therapeutic, antiseizure effect of drugs that promote BBB repair. We also present BBB neuroimaging as a tool to correlate BBB restoration to seizure mitigation. Add‐on cerebrovascular drug could be of efficacy in reducing seizure burden when used in association with neuronal antiepileptic drugs.
Summary
Objective
To report the presurgical workup, surgical procedures, and outcomes in a series of pediatric patients with drug‐resistant epilepsy involving the perisylvian/insular regions.
Methods
...We retrospectively assessed 16 pediatric patients affected by drug‐resistant focal epilepsy involving perisylvian/insular regions, who consecutively underwent tailored resective surgery. All patients underwent a detailed presurgical workup, which included the analysis of the anatomoelectroclinical correlations with scalp electroencephalography (EEG) and/or with stereo‐electroencephalography (SEEG), brain magnetic resonance imaging (MRI), and comprehensive cognitive and neuropsychological evaluations. After surgery, all patients underwent serial clinical and laboratory evaluations.
Results
Focal motor seizures restricted to perioral area, associated with symptoms related to the surrounding areas (as auditory hallucinations, unpleasant paresthesia, fear, and epigastric sensation), characterized the ictal semiology in 75% of patients. In 50%, autonomic manifestations were present and in 56% subjective manifestations were reported. The 50% of the patients underwent SEEG with insular sampling to better define the epileptogenic zone. In all patients, the insular cortex was always part of the epileptogenic zone, and tailored resections also involved, with variable degree, the frontal, parietal, and temporal opercula. Preoperatively, the neuropsychological assessment revealed impairments in specific cognitive functions and mild or moderate cognitive compromise in 88% of the patients. Postoperatively, one patient had permanent slight hemiparesis. At the most recent follow‐up (median 39 months), seizure outcome was satisfactory in 69% of patients: seven patients were completely seizure‐free (Engel class Ia), two were free of disabling seizure (class Ic), and two had rare disabling seizures (class II). The cognitive functioning remained unchanged in 62%, and improved in 38%.
Significance
The assessment of perisylvian/insular epilepsy in children is particularly challenging. However, tailored resections based on a careful presurgical evaluation, including SEEG recording, may lead to a good seizure control and to a better overall outcome.
Summary
A pathogenic role of immunity in epilepsies has long been suggested based on observations of the efficacy of immune‐modulating treatments and, more recently, by the finding of inflammation ...markers including autoantibodies in individuals with a number of epileptic disorders. Clinical and experimental data suggest that both innate and adaptive immunity may be involved in epilepsy. Innate immunity represents an immediate, nonspecific host response against pathogens via activation of resident brain immune cells and inflammatory mediators. These are hypothesized to contribute to seizures and epileptogenesis. Adaptive immunity employs activation of antigen‐specific B and T lymphocytes or antibodies in the context of viral infections and autoimmune disorders. In this article we critically review the evidence for pathogenic roles of adaptive immune responses in several types of epilepsy, and discuss potential mechanisms and therapeutic targets. We highlight future directions for preclinical and clinical research that are required for improved diagnosis and treatment of immune‐mediated epilepsies.
Objective
Dravet syndrome (DS) is a drug‐resistant, infantile onset epilepsy syndrome with multiple seizure types and developmental delay. In recently published randomized controlled trials, ...fenfluramine (FFA) proved to be safe and effective in DS.
Methods
DS patients were treated with FFA in the Zogenix Early Access Program at four Italian pediatric epilepsy centers. FFA was administered as add‐on, twice daily at an initial dose of 0.2 mg/kg/d up to 0.7 mg/kg/d. Seizures were recorded in a diary. Adverse events and cardiac safety (with Doppler echocardiography) were investigated every 3 to 6 months.
Results
Fifty‐two patients were enrolled, with a median age of 8.6 years (interquartile range IQR = 4.1‐13.9). Forty‐five (86.5%) patients completed the efficacy analysis. The median follow‐up was 9.0 months (IQR = 3.2‐9.5). At last follow‐up visit, there was a 77.4% median reduction in convulsive seizures. Thirty‐two patients (71.1%) had a ≥50% reduction of convulsive seizures, 24 (53.3%) had a ≥75% reduction, and five (11.1%) were seizure‐free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA.
Significance
In this real‐world study, FFA provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated.
Targeting pro-inflammatory events to reduce seizures is gaining momentum. Experimentally, antagonism of inflammatory processes and of blood-brain barrier (BBB) damage has been demonstrated to be ...beneficial in reducing status epilepticus (SE). Clinically, a role of inflammation in the pathophysiology of drug resistant epilepsies is suspected. However, the use anti-inflammatory drug such as glucocorticosteroids (GCs) is limited to selected pediatric epileptic syndromes and spasms. Lack of animal data may be one of the reasons for the limited use of GCs in epilepsy. We evaluated the effect of the CG dexamethasone in reducing the onset and the severity of pilocarpine SE in rats. We assessed BBB integrity by measuring serum S100β and Evans Blue brain extravasation. Electrophysiological monitoring and hematologic measurements (WBCs and IL-1β) were performed. We reviewed the effect of add on dexamethasone treatment on a population of pediatric patients affected by drug resistant epilepsy. We excluded subjects affected by West, Landau-Kleffner or Lennox-Gastaut syndromes and Rasmussen encephalitis, known to respond to GCs or adrenocorticotropic hormone (ACTH). The effect of two additional GCs, methylprednisolone and hydrocortisone, was also reviewed in this population. When dexamethasone treatment preceded exposure to the convulsive agent pilocarpine, the number of rats developing status epilepticus (SE) was reduced. When SE developed, the time-to-onset was significantly delayed compared to pilocarpine alone and mortality associated with pilocarpine-SE was abolished. Dexamethasone significantly protected the BBB from damage. The clinical study included pediatric drug resistant epileptic subjects receiving add on GC treatments. Decreased seizure frequency (≥ 50%) or interruption of status epilepticus was observed in the majority of the subjects, regardless of the underlying pathology. Our experimental results point to a seizure-reducing effect of dexamethasone. The mechanism encompasses improvement of BBB integrity. Our results also suggest that add on GCs could be of efficacy in controlling pediatric drug resistant seizures.
Purpose: It is generally accepted that blood–brain barrier (BBB) failure occurs as a result of CNS diseases, including epilepsy. However, evidences also suggest that BBB failure may be an etiological ...factor contributing to the development of seizures.
Methods: We monitored the onset of seizures in patients undergoing osmotic disruption of BBB (BBBD) followed by intraarterial chemotherapy (IAC) to treat primary brain lymphomas. Procedures were performed under barbiturate anesthesia. The effect of osmotic BBBD was also evaluated in naive pigs.
Results: Focal motor seizures occurred immediately after BBBD in 25% of procedures and originated contralateral to the hemisphere of BBBD. No seizures were observed when BBB was not breached and only IAC was administered. The only predictors of seizures were positive indices of BBBD, namely elevation of serum S100β levels and computed tomography (CT) scans. In a porcine model of BBBD, identical procedures generated an identical result, and sudden behavioral and electrographic (EEG) seizures correlated with successful BBB disruption. The contribution of tumor or chemotherapy to acute seizures was therefore excluded.
Conclusion: This is the first study to correlate extent of acute BBB openings and development of seizures in humans and in a large animal model of BBB opening. Acute vascular failure is sufficient to cause seizures in the absence of CNS pathologies or chemotherapy.
Abstract Status epilepticus (SE) is one of the most serious manifestations of epilepsy. Systemic inflammation and damage of blood-brain barrier (BBB) are etiologic cofactors in the pathogenesis of ...pilocarpine SE while acute osmotic disruption of the BBB is sufficient to elicit seizures. Whether an inflammatory-vascular-BBB mechanism could apply to the lithium–pilocarpine model is unknown. LiCl facilitated seizures induced by low-dose pilocarpine by activation of circulating T-lymphocytes and mononuclear cells. Serum IL-1β levels increased and BBB damage occurred concurrently to increased theta EEG activity. These events occurred prior to SE induced by cholinergic exposure. SE was elicited by lithium and pilocarpine irrespective of their sequence of administration supporting a common pathogenetic mechanism. Since IL-1β is an etiologic trigger for BBB breakdown and its serum elevation occurs before onset of SE early after LiCl and pilocarpine injections, we tested the hypothesis that intravenous administration of IL-1 receptor antagonists (IL-1ra) may prevent pilocarpine-induced seizures. Animals pre-treated with IL-1ra exhibited significant reduction of SE onset and of BBB damage. Our data support the concept of targeting systemic inflammation and BBB for the prevention of status epilepticus.
The causes of genetic epilepsies are unknown in the majority of patients. HCN ion channels have a widespread expression in neurons and increasing evidence demonstrates their functional involvement in ...human epilepsies. Among the four known isoforms, HCN1 is the most expressed in the neocortex and hippocampus and de novo HCN1 point mutations have been recently associated with early infantile epileptic encephalopathy. So far, HCN1 mutations have not been reported in patients with idiopathic epilepsy. Using a Next Generation Sequencing approach, we identified the de novo heterozygous p.Leu157Val (c.469C > G) novel mutation in HCN1 in an adult male patient affected by genetic generalized epilepsy (GGE), with normal cognitive development. Electrophysiological analysis in heterologous expression model (CHO cells) and in neurons revealed that L157V is a loss-of-function, dominant negative mutation causing reduced HCN1 contribution to net inward current and responsible for an increased neuronal firing rate and excitability, potentially predisposing to epilepsy. These data represent the first evidence that autosomal dominant missense mutations of HCN1 can also be involved in GGE, without the characteristics of epileptic encephalopathy reported previously. It will be important to include HCN1 screening in patients with GGE, in order to extend the knowledge of the genetic causes of idiopathic epilepsies, thus paving the way for the identification of innovative therapeutic strategies.
•We have identified a new heterozygous de novo mutation of HCN1 (p.L157V) in a patient with genetic generalized epilepsy (GGE).•The L157V mutation reduces the HCN1 current in both CHO cell and neonatal neurons, in a dominant manner.•When expressed in neurons, mutant channels reduce the firing threshold and increase excitability.•This is the first evidence that loss-of-function HCN1 mutations can predispose to GGE.
We report the clinical and EEG data of two patients harboring heterozygous
mutations, who presented with typical absence seizures at 3 Hz spike and wave as well as with mild cognitive disability. ...Neuroradiological and other laboratory investigations were normal. Our observations suggest that
mutations can be suspected in children with typical absences as the only seizure type, especially if associated with, even mild, cognitive deficits.
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